title: Structural and mechanistic insights into the arginine/lysine-rich peptide motifs that interact with P97/VCP.
abstract: P97 protein, also referred to as valosin-containing protein (VCP), is an AAA-ATPase (ATPase associated with a variety of cellular activities) that mediates vital cellular activities with the cooperation of many cofactors. A group of cofactors interact with the N-terminal domain of P97 (P97N) through their Arg/Lys-rich peptide motifs. We investigated the interactions between P97 and these motifs, including VCP-binding motif (VBM) and VCP-interacting motif (VIM). The solution structures of the VBM motif from HRD1 and the VIM motif from SVIP are both comprised mainly of a single α-helix. The VIM motifs generally have stronger P97N-binding affinities than the VBMs, and SVIP (VIM) can compete with HRD1-VBM for the interaction, providing a possibility that VIM-containing proteins (such as SVIP) act as competitors against VBM-containing proteins (such as HRD1) for interacting with P97. Based on biochemical features of the VBM motifs, we also identified NUB1L (NEDD8 ultimate buster-1 long) as a novel VBM-containing protein, which is involved in proteasomal degradation of NEDD8 through the P97 pathway.
authors.affiliation: State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Liu
authors.forename: Qing-Shan
authors.initials: QS
authors.lastname: Fu
authors.forename: Jian
authors.initials: J
authors.lastname: Zhao
authors.forename: Hong-Yu
authors.initials: HY
authors.lastname: Hu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000251:Adenosine Triphosphatases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020816:Amino Acid Motifs; D001120:Arginine / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000075687:NEDD8 Protein; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D028044:Phosphate-Binding Proteins; D011392:Proline / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D059748:Proteolysis; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014452:Ubiquitins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000074405:Valosin Containing Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D008565:Membrane Proteins; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; C430242:NUB1 protein, human; D010455:Peptides; D028044:Phosphate-Binding Proteins; C569017:SVIP protein, human; D014157:Transcription Factors; D014452:Ubiquitins; D001120:Arginine; D011392:Proline; C482345:SYVN1 protein, human; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein
keywords: AAA; ATPase associated with a variety of cellular activities; Arginine/lysine-rich; BS1; ERAD; ITC; Interaction; NMR; P97-ND1; P97/VCP; P97N; Structure; VBM; VCP; VCP-binding motif; VCP-interacting motif; VIM; binding site 1; endoplasmic reticulum-associated degradation; isothermal titration calorimetry; nuclear magnetic resonance; the N and D1 domains of P97 (residues 1–458); the N-terminal domain of P97 (residues 1–213); valosin-containing protein